The overall goal of the Center for Craniofacial Development and Disorders is to increase our knowledge of the normal process of cranial development and the pathogenesis of craniosynostosis. Craniosynostosis, the premature fusion of calvarial suture(s) resulting in abnormal skull shape, is a major health problem. It occurs in 1/3000 newborns of all ethnic and racial populations, and in moderate to severe cases if uncorrected, can impede growth of the brain causing secondary neurologic, respiratory, auditory, and ocular deficits. Little is known at the molecular level about the formation of the normal cranium and the cause of over 90 craniosynostotic conditions, of which at least 50 are genetic. To advance our understanding of this common developmental defect, the Center will study normal and abnormal cranial development from the phenotypic to the molecular level using a multidisciplinary and interactive team approach. The Center is structured with 3 Cores and 5 Projects. The Cores consist of Administrative Core I; Clinical Core II where over 500 craniosynostotic patients in the greater Baltimore are will be clinically examined and diagnosed, undergo 3D CT scans and chromosomal and DNA analyses; and DNA Core III which will perform oligonucleotide synthesis, polymorphism and mutation analysis, DNA sequencing, gene mapping, and histologic gene expression studies. Project I will conduct an epidemiologic study of these patients to determine environmental and genetic risk factors; Project II will analyze postnatal cranial development by using data from 3D CT scans from subgroups of patients with isolated sagittal and isolated coronal synostosis and compare them to normals; Project III will isolate genes involved in normal craniofacial development by cDNA subtractive hybridization, direct selection and exon trapping of the chromosome 7p region where at least 2 craniosynostotic genes have been identified, and screening for homologous MSX genes which are involved in calvarial development; Project IV will isolate the gene responsible for the most common craniosynostotic genetic syndrome, Saethre-Chotzen, and other craniosynostotic genes from patients with chromosome del (7p); and Project V will study the transcriptional characteristics of the MSX gene and the mechanism by which this mutant gene causes craniosynostosis. Through these epidemiologic, morphologic, developmental and molecular studies a better understanding of cranial development and clinical diagnosis and management of craniosynostosis will be achieved.